MXPA97005609A - Composite of bism - Google Patents

Abstract

The use in the formation of diagnostic images, in particular X-rays, MRI, ultrasound and scintigraphy, of contrast agents consisting of bismuth groups and / or organic bismuth compounds, and a contrast medium containing such bismuth compounds . The bismuth compounds are also useful in therapy, in particular as antimicrobial agents and as antiulcer agents. New bismuth compounds are also revealed

Description

BISMUTO COMPOSITES FIELD OF THE INVENTION The present invention relates to the use in the formation of diagnostic images, in particular X-rays, MRI, ultrasound and graphigraphy, of contrast agents consisting of bismuth aggregates and / or organic bismuth compounds, and a medium of contrast containing such bismuth compounds. Another aspect of the present invention is the use of the bismuth compounds in therapy, in particular as antiulcer agents.

BACKGROUND OF THE INVENTION All image formation for diagnosis is based on the achievement of different levels of signals from the different structures within the body. Thus, in the formation of X-ray images, for example, for a given body structure to be visible in the image, the attenuation in the X-rays of the structure may differ due to the surrounding tissues. The difference in signal between the structure of the body and these surroundings is often a delayed contrast, and many efforts have been devoted to means to intensify the contrast in the formation of i-EF: 25275 genes for diagnosis based on the most Great between a structure of the body and its surroundings, the highest quality of the images and the greatest of its values when carrying out a medical diagnosis. In addition, the contrast-larger of the smaller structures of the body that can be visualized in the procedure of image formation, i.e. an increase in contrast can lead to an increase in spatial resolution. The quality of the images in diagnosis depends, in large part, on the level of noise inherent in the imaging procedure - the ratio of the contrast level to the noise level can thus represent a quality factor in diagnosis effective for the formation of images in diagnosis. Improvements have been made in such a quality factor in diagnosis and yet an important goal is lacking. In techniques such as X-rays and ultrasound, a proposal to improve the quality factor in diagnosis has been to introduce materials that increase the contrast, contrast agents, in the region of the body that will be projected. Thus in X-rays, for example, first examples of contrast agents, were insoluble inorganic barium salts which increased the attenuation of X-rays in the zoos of the body in which these salts were distributed. Recently the field of X-ray contrast agents has been dominated by compounds containing soluble iodine such as those marketed by Nycomed AS under the R-R registered names Omnipaque and Visipaque. Many recent works on X-ray contrast agents have concentrated on aminopolycarboxylic acid (APCA), heavy metal ion chelates and, recognizing that effective imaging of many body sites requires localization at the sites of the body. In a relatively large body of metal ions, it has been suggested that polychelants, which are substances that have more than one separate chelating moiety, can be used to achieve this purpose. Several bismuth compounds have been suggested in prior art as X-ray absorbing agents. Other previous documents have focused on the use of metal chelates in diagnostic imaging, especially in MRI. In addition, bismuth compounds have a long history in therapeutic medicine, especially in the treatment of gastrointestinal disorders, such as ulcers. Although anti-ulcer agents such as the H-antagonists cimetidine and ranitidine, and more recently inhibitors that drive protons such as omeprazole, have been developed, there is, however, the medical use of bismuth compounds in the treatment of ulcers. The bismuth compounds most commonly used as gastrointestinal drugs are, today, the bismuth subnitrate and the bismuth subsalicylate. The bismuth nitrate nitrate of bismuth hydroxide (Bic.O (OH), (NO)) is prepared by hydrolysis of bismuth nitrate and is practically insoluble in water, which is usually used as a suspension. (Bismuth slurry.) Bismuth subnitrate is also used topically in lotions and ointments.The bismuth subsalicylate or basic bismuth salicylate (C.HBÍO) 7 5 4 is also practically insoluble in water, and is administered as a Suspension or in the form of tablets Products containing bismuth subsalicylate are used against indigestion, nausea and diarrhea As an antidiarrheal agent, this shows good activity against Seilonella, with less activity against E. coli Various bismuth compounds They are known to be biologically active and have been suggested as active ingredients in various drug formulations.The organo-bismuth compounds can be used as antibacterial agents, for example with tra infections caused by highly resistant gram-negative bacteria (US 3,466,366 of M & amp;; T Chem Inc); A complex of bismuth-type protein, is suggested for the treatment of inflammation and infections in the gastrointestinal system in US 4,153,685 (Schering Corp) derivatives of bismuthlprostanoate for the control of ulcers, is suggested in BE 809388 (Aries R ); bis (2-pyridinetiol) 1-phenyl bismuth oxide as an antibacterial agent and as an antifungal agent is disclosed in US 3,824,307 (Procter &Gamble Co.); an anti-inflammatory and anti-inflammatory bismuth composition containing a mixture of trivalent bismuth, soluble protein in water, an organic acid anion and an alkali in ZA 8107456 (Schering Corp); bismuth subsalicylate in combination with other agents in a synergistic formulation for the treatment of diarrhea in US 4,588,589 (Richardson Vicks); treatment of non-ulcerative dyspepsia associated with Campylobacter pi-loridis (infection) with bismuth salts such as tripotassium dicitrate bismutate in WO 89 / 032L9 (Borody T. J.); organo-bismuth compounds useful as anti-coccid agents for poultry; and as insecticides in J63225391 (Nitto Ka-sei and Shionogi); pharmaceutical compositions for the treatment of gastrointestinal disorders associated with Campylobacter pylori (infections) consisting of a pharmaceutically acceptable bismuth compound and antimicrobial agents or primary and secondary antibiotics in EP 439453 (Capability Services et al.); salts formed between rantidine and bismuth carboxylic acid complexes for the treatment of gastrointestinal disorders in US 5,008,256 (Glaxo); other salts formed between a H-receptor antagonist and a bismuth complex with a carboxylic acid with activity against gastrointestinal conditions and against Campylobac er pilori in US 5,273,984 (Glaxo); a suspension for oral administration consisting of a pharmaceutical agent containing bismuth, benzoic acid and sorbic acid, polymer and water for use against various gastrointestinal disorders in US 5,013,560 (Procter &Gamble); furan derivatives with bismuth carboxylic acid complexes for the treatment of various gastrointestinal disorders including activity against Heliobacter pylori in US 5,229,418 (Glaxo); bismuth polyacrylate complexes for the treatment of gastrointestinal disorders such as, for example, inflammatory bowel disease or infections by Heliobacter pylori in WO 92/01457 (Evans B. K. et al.); salts of ranitidine with a bismuth carboxylate complex and alkali salt for the treatment of various gastrointestinal disorders in GB 2248185 (Glaxo); use of the bismuth citrate of rantidine and antibiotics to inhibit Heliobacter pylori in EP 533281 (Glaxo); and ranitidine bismuth citrate and non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases in GB 2262036 (Glaxo). Finally, W0 95/06053 discloses certain substituted triphenyl bismuth compounds as contrast agents for X-rays.

DESCRIPTION OF THE INVENTION We have found that certain bismuth compounds provide an increase in contrast, particularly effective, when used as contrast agents. Some of these compounds can also be used in the treatment of various gastrointestinal disorders. Thus, one aspect of this invention is a contrast medium for diagnostic imaging which comprises a covalent bismuth compound of the type that does not form aggregates. Such a medium can be used to increase the contrast in diagnostic imaging, in particular in X-rays, MRI, imaging for ultrasound and graphigraphy. For X-rays or imaging for ultrasound, it is preferred that the compounds include two or more heavy atoms, wherein at least one of the heavy atoms is bismuth. For the sake of clarity, the word "heavy atom" means a bromine atom or an atom with an atomic number greater than 49. For MRI, the compounds will include bismuth atoms and one or more MR active atoms. For the purpose of clarity, the words "active atom MR" means an atom that directly or indirectly affects the MR signal. Typical MR active atoms include, for example, panganese, gadolinium, dysprosium, iron and fluorine. The invention provides, for example, a contrast medium for diagnostic imaging which comprises a physiologically tolerable molecule of any of the formulas I-IV: (II) (i) (III) (IV) where the R-R- groups. they may be the same or different 1 b and are defined as any group that forms a hydrolytically stable bond to bismuth. Characteristic groups R.sup.1 - are preferably aryl groups substituted with one or more heavy atoms, preferably Bi and I. X is 0, S or NR_ in or where R_ is lower alkyl, for example C-alkyl. ., alkyl 1-4 under sutituido or an aryl group. Viewed from another aspect, the invention provides a contrast medium for diagnostic imaging which consists of a non-covalent bismuth compound of the non-aggregated type, with the proviso that the bismuth compound contains at least one additional heavy atom The additional heavy atom in such non-covalent compounds of the non-aggregate type can be covalently or non-covalently bonded and can, for example, be an iodine atom. The compound may contain more than one non-covalently linked bismuth atom, for example 2 or 3 such atoms or up to 10 or more such atoms.

Viewed from another aspect, the invention provides a contrast medium for diagnostic imaging which comprises a physiologically tolerant multinuclear bismuth complex of formula V, (MBA) L (V) mnpxy wherein MBA is a multinuclear entity wherein each M mnp which may be the same or different, is a heavy metal atom that increases the contrast and at least one M is Bi (and preferably each M is Bi) and each M is covalently linked to at least one B atom when n is non-zero; each B, which may be the same or different, is a non-metallic bridged atom covalently linked to at least-two M atoms and optionally to other atoms; each A, which may be the same or different, is a non-bridged non-metallic atom covalently linked to an M atom; each L, which may be the same or different, is a ligand co-ordinately linked to at least one atom of Bi; m is a positive integer of value 2 or greater; n, p and "and" are independently zero or positive integers whenever n and p are not simultaneously zero; x is a positive integer; or a physiologically tolerable salt thereof, together with at least one pharmaceutical excipient. Seen from another aspect, the invention also provides the use of bismuth compounds, as defined above, for the preparation of a contrast medium to be used in the image formation of the human or non-human body. Seen from another aspect, the invention provides a method for generating an image of a human or non-human body, preferably a mammal, wherein the method comprises the administration to said body of a physically tolerable amount that increases the contrast, of a bismuth compound as defined above and generate an image of at least a part of said body in which said agent is distributed, eg by X-rays, MRI or formation of images by ultrasound or graphigraphy. Viewed from another aspect, the invention also provides a contrast medium for diagnostic imaging which comprises a bismuth compound, as defined above, together with at least one sterile pharmaceutical carrier or excipient. Seen from another aspect, the invention also provides the use of the bismuth compounds which form aggregates and of the covalent bismuth compounds which do not form aggregates, as defined above, for the preparation of therapeutic agents for the treatment of gastrointestinal disorders. , for example caused by Heliobacter pylori Viewed from another aspect, the invention provides a method for the treatment of a gastrointestinal disorder, for example caused by Heliobacter pylori, of a human or non-human body, preferably a mammal, where the method comprises administering to said body a physiologically tolerable dose of a bismuth compound which forms -added or a covalent bismuth compound which does not form -added as defined above. The bismuth compounds defined above have a particular potential as contrast agents, since the compounds have a relatively high concentration of heavy elements including bismuth. The use of these compounds allows a high proportion of the atom that increases the contrast to the total volume of the structure to be achieved. In this way, by increasing the laughing content of atoms that increase the contrast in this sense, the total amount of the contrast agent needed to achieve the same contrast effect can be reduced and thus evoke problems associated with the solubility of the contrast agent. -contrast or toxicity or osmolality thereof, or with the -viscosity of the contrast medium, can also be reduced. As mentioned above, it is preferred that the bismuth compounds of the invention include two or more atoms that increase the contrast. Both the covalent bismuth molecules and the chelates of multinuclear aggregates also contain other atoms which may have little or no effect to increase the contrast, but which can, for example, function as bridged atoms by linking -the atoms that increase the contrast together in an aggregate (see WO 92/17215 for other examples of these types of structures). Other non-contrast active atoms in the contrast agent, for example, function as detoxification groups, as solubilizing groups, in groups for the purpose of the bismuth atom and the other active atoms-contrast to the area of interest, or active atoms that do not form aggregates help to stabilize the covalent molecule or chelate - against hydrolysis and metabolism. The bismuth compounds described above can, as noted above, be used in various modalities in medical imaging and in certain specific therapeutic fields. Some bismuth compounds are active in more than one modality. The choice of modality will be carefully taken into consideration in the design of the agent. For example, if the agent is projected for use in MRI, active elements MR such as fluorine and / or paramagnetic elements such as manganese or gadolinium, preferably part of the molecule. So, one of the most interesting applications of these compounds that contain bismuth, is in the formation of images by X-rays. To be used as a contrast agent in X-rays, it is preferred that the compounds contain bismuth and at least one additional heavy atom. Preferred bismuth compounds can, in addition to bismuth, contain atoms such as bromine, iodine, lanthanides, transition metals, or other metal atoms. Examples include Gd, Ce, Sr, Y, Zr, Ru, Rh, In, Ta, Nb, Dy, Hf, W, I, Mo, Re, Os, Pb, Ba Ga, Sn, Hg, and TI. Bismuth compounds containing several bismuth atoms and / or several iodine atoms are more preferred. The choice of the heavy atom and the number of atoms killed in each unit are determined by a variety of factors including the toxicity of the molecule as a whole or the toxicity of the complex that forms aggregates, stability in vitro and in vivo (permanence in a shelf) of the unit and the absorption characteristics of the X-rays of the heavy atom. In this regard it will have been noted that although the absorption of the X-rays in the cross-section for atoms generally increases with the increase in the atomic number, the absorption in the cross-section is likewise dependent on the wavelength of the beam. X and increases with an increase in photon energy until it reaches slightly above a later value of the K-edge at which point the attenuation decreases. Thus, there are energy zones of the photon for which one element is a better X-ray attenuator than a second, although in the higher zones of this energy the second element may be the best attenuator. Accordingly, the bismuth compounds according to the invention will each have optimum foothone energy zones, then being profiled particularly suitable for operation with X-ray imagery apparatus using X-rays having such Photon energy zones. So, for the choice of bismuth compounds that contain atoms of more than one heavy element, -one can create contrast agents for X-rays that have an optimal functioning in more than one band of energy of the photon or on one band. wide. The compounds used in accordance with the present invention are thus particularly attractive since they can be selected to match their X-ray attenuation profiles with the X-ray emission profiles of particular sources. X-ray - in effect, the invention provides a contrast medium for X-rays which can be "attenuated". From an efficiency point of view, bismuth and uranium are heavy atoms with the highest efficiency per atom in all X-ray modalities (CT, clear X-rays and DSA). In the previous formulas I - IV, R.-R-. they can be the same or different, and they can be any group that forms a hydrolytically stable bond to bismuth. Characteristic groups R ..- R-. they may be, for example, aryl groups, optionally substituted with one or more heavy atoms such as Bi and I. For extracellular X-ray contrast agents, the Ri c groups are usually substituted with one or more (preferably more) hydrophilic groups. Such compounds have, in general, a low charge or preferably no charge The bismuth link to one of the R. groups. can - 1 - b be, for example, of the following types: Bi-C, Bi-O, Bi-S and Bi-N. Some of these links are more stable than others and it is known from literature about the chemistry of bismuth, that the stability of the bismuth molecule is very dependent on the chemical nature of this link and on the chemical nature of the substituents . (see for example Chapter 28 in G. Wilkinson (ed) Comprehensive Coordination -Chemistry; Gmelin Handbuch der Anorganischen Chemie Volume 47 LD Freedman and G. 0. Doak in Chem. Rev (1982) 82 15-57; Mehoden der Organischen Chemie ( Houben-Weyl) Volume XIII / 8, Comprehensive Organometallic Chemistry, Chapter 13, Kirk-Othmer: Encyclopedia of Chemical Technology Volume 3 pp 921-936). Some trialkyl bis compounds are known to be very hydrolytically unstable, so we have found that triaryl bismuth compounds are surprisingly stable against hydrolysis: triphenyl bismuth dissolved in aqueous tetrahydrofuran (25%) is stable under reflux for many days. When groups R.,. form Bi-C bonds, aryl groups 1- are generally preferred. At least one of the groups R. _ will be an aryl group or substituted aryl group. The term "aryl group" here means any ring system of an aromatic hydrocarbon or heterocyclic aromatic system. Characteristic ring systems include, for example, benzene, naphthalene, indene, fluorene, phenalene, phenanthrene, anthracene, fluoranthene, acefenanthylene, aceanthylene, triphenylene, pyrene, chrysene, naphthacene, pleiadene, picenum, perylene, pentaphene, pentacene, tetraphenylene, hexaphene, hexacene, rubiceno, -coronene, trinaphthylene, heptaphene, rubiceno, coronenne, heptacene, pyrantrene, ovalene, furan, thiophene, thiantrene, pyran, isoben-zofuran, chromene, xanthene, phenoxathine, pyrrole, imidazole, pyrazole, isothiazole , isoxazole, pyridine, pyrazine, pyrimidine, pyradi zine, indolizine, isoindol, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphyridine, quinoxaline, quinazoline, cinnoline, teridine, carbazole, B-carboline, phenanthridine na, acridine, permidine, phenanthroline, phenazine, fenarsazine, faith notiazine, furazano, phenoxazine, isochroman, chroman, indoline and iso-indoline. Possible alkyl groups include both high and low substituted or unsubstituted alkyl, alkoxy, polyalkoxy and alkylaryl groups, or any other groups. The R groups can be substituted with contrast elements or contrast active groups, and other e-lements or active groups of non-contrast. Characteristic active contrast elements were listed above. The most preferred active contrast elements for X-ray imaging are iodine and bismuth. Other substituents include fluorine, chlorine, bromine, alkyl, alkoxy, substituted alkyl, for example, hydroxyalkyl or polyhydroxyalkyl, -alkoxy substituted, for example, hydroxyalkoxy or polyhydroxyalkoxy, amides, including substituted amides such as -NAcR_ and or -C0NR "wherein Ac is an acyl group and R_-RQ, which may be the same or different, represent lower alkyl, hydroxyalkyl-C, carboxy or amino-C-alkyl or together both R" and RQ , represent a cyclic group such as -CH_CH "NR- / s ¿9 CHnCH - where RO, for example, is an alkyl-C group, ¿L ¿. and 1-4 optionally substituted by hydroxyl, carbonyl, aryl or amino groups. Particularly convenient, multi-nuclear bismuth complexes are presented as their complex chelates containing EDTA or other APCAs. Such chelate complexes are remarkably stable taking into consideration the release of heavy metal ions. It is particularly preferred that the electrical charge conducted by the portions of the complex be substantially, if not completely, balanced to that carried by the complex entity; for APCA chelators, this can be easily achieved, for example, by omission, replacement or deactivation (e.g. by the formation of an ester or amide) of one or more of the carboxyl portions. Many suitable chelants are well known or have been described in the literature, especially literature relating to heavy metal detoxification agents, bi-functional chelating agents and chelating agents based on a chelate, eg those described in WO-A-89/00557 ( Berg) and the documents mentioned therein and in the search report attached to e-11o, US-A-4647447 (Gries), US-A-4826673 (Dean), EP-A-230893 (Felder), EP-A -217577 (Frincke), US-A-4652519 (Warshawsky), US-A-4687659 (Quay), and numerous recent publications of -patents of Nycomed AS, Salutar Inc, Schering AG, Squibb, Bra eco, Mallinckrodt, Dow and Guerbet. While polyamines, especially linear or cyclic polyamines, such as ethylenediamine, 1,4,7-triazacyclononane and cyclin, can be used as chelators, in general APCAs are preferred, particularly DTPA, EDTA and derivatives thereof, and other APCAs cyclic and non-cyclic as defined in WO-A-89/00557. Examples of suitable chelators include compounds of -formulas: (HOOCCH2) 2NCH2CH2N (CH2COOH) 2 (i) (HSCH2CH2) 2NCH2CH2N (CH2CH2SH) 2 (ii) H2NCH2CH2N (CH2COOH) CH2CH2N (CH2C00H) CH2CH2H2 (iii) H2NCH2CH2N (CH2CH2SH) CH2CH2N (CH2CH2SH) CH2CH2NH2 (iv) H00CCH2 (NCH2CH2) 3NCH2COOH (v) HSCH2CH2 (NCH2CH2) 4SH ( i) (where y = 6, 7, 8, 9, or 10 and z = 0 or 1) (HOOCCH2) 2NH (iii) (HSCH2CH2) 2NH (ix) (HOOCCHj) 2NCH2CH2N (CH2C00H) CH2CH2N (CH2COOH) CH2CH2N (CH2COOH) 2 (X) (HSCH2CH2) 2NCH2CH2N (CHJCHJSH) CHJCHJN < CH2CH2SH) CH2CH2 (CH2CH2SH) 2 (xi) (HOOCCH2) 2N (CH2CH2NH) 2CH2CH2N. { CH2COOH) 2 (xii) (HSCH2CH2) 2N (CH2CH2NH) 2CH2CH2N (CH2CH2SH) 2 (xiii) pyridine-2,6-dicarboxylic acid (xiv) 2,6-bis-mercaptomethyl-pyridine (XV) tetra-N-alkyl-ethylenediamine (xix) penta-N-alkylIdietilaaolstiai-iina (xx) and the phosphorus analogues of these ligands based on donor-genomic nitro.

Chelators such as NTA, IDA, EDTA, HEDTA, DTPA, DTPA-BMA, HEDDA, TTDA, EDTA-BMA, TBEDDA, MEEDDA, TTHA, EDDA, EHPG, PDTA, CHDTA, HPDTA and triazacyclononane monoacetic acid, especially PDTA and EDTA, They are of particular interest. Particularly preferred chelators include cyclin, EDTA, DTPA, DOTA, D03A, HP-D03A, the 6-oxa and 6-thia analogues of the -DTPA and amides thereof, e.g. DTPA-BMA and DTPA-BMO (acid 6-carboxymethyl-3,9-bis (morpholinocarbonyl-methyl) -3,6,9-triazoundeca nodioico - the chelate Gcl (III) of which is sometimes re ] -0 ferido as gadopenamide). When the chelate corresponds to a macromolecule, there can conveniently be any tissue, organ or target cell of the macromolecule, for example a biomolecule such as a protein, an antibody or a fragment of an anti-body, or alternatively it can be a biological and relatively inert material such as a polysaccharide or poly-sugar alcohol, eg dextran or starch. Such macromolecules are discussed extensively in recent literature related to contrast agents. The bismuth compounds used according to the invention may be ionic or, more preferably, may not carry net charge; more preferably, the compound is non-ionic. In addition, these compounds can be soluble in water or, less preferably, insoluble in water. Compounds with low solubility in water can be used as contrast agents in X-rays for the imaging of the liver, the spleen, in the accumulation of lymphatic blood and the gastrointestinal system. Water-soluble macromolecule bismuth compounds (p.m. greater than 20,000) can be used as contrast agents in X-rays for blood collection. Any counter-ions necessary - must of course also be, more preferably, physiologically tolerable. The scope of the counterions physiologically acceptable to therapeutically active bismuth agents is, of course, well known to pharmacologists. Suitable counterions include, for example, protons, alkali and ions of alkaline earth metals, e.g. Sodium, calcium and magnesium and zinc, ammonium and organic cations (eg organic amine cations, organic amine cations iodata-two, quaternary ammonium, pyridinium, meglumine, alkylammonium, p-lihydroxy-alkylammonium, protonated amino basic acids, etc.) cations of transition metal complexes and organometallic cations. Suitable counterions also include, for example, halide (e.g. chloride, bromide, iodide and I). The invention also provides covalent bismuth compounds of the non-aggregated type, with the proviso that when the bismuth compound is a triphenyl bismuth compound it contains at least one additional heavy atom, or at least one of the phenyl groups is substituted. in at least four of its ortho, meta and para positions, and the molecule as a whole contains at least one hydroxy group or a carboxyl group. Preferably, the compounds also contain at least one covalently linked (additional) bismuth atom or at least one covalently bonded iodine atom. This invention, in this manner, provides novel bismuth compounds of formula I which can be represented as follows: (ig) (If) (Ih) R in the formulas (la) - (Ih) can be the same or -different. Characteristic groups R can be, for example A-. peep: -COOH, -NHCOCH, -N (Me) COCH3 / -CONHCH3, -CO HCH2CH2OH, -CONHCH2CO HCH3 / - NHCOCHOHCH ,, -NHCOCH2OCH3 / - CONHCH2CHOHCH2OH,. - CON (Me) CH 2 CHOHCH 2 OH, - CONHCH (CH 2 CH 2 OH) 2, - CONHCH (CH 2 OH) 2 CHOHCHjOH, -CONHCH (CH 2 OH) .CHOH. CHOH CH 2 OH, -OCH 2 CH 2 OH, -NHCOCHjOH, -CH 2 OH and N (COCH 2 OH) (CH 2 CH 2 OH).

This invention also provides novel bismuth compounds of formula II which may be represented as follows: (He) R -R in the formulas (lia) - (líe), they may be the same or different and characteristic groups R were listed above. BG can be any bridged group. In the compounds of the invention, the linking group BG is conveniently a 1, 2 or 3 membered chain which consists of carbon, nitrogen, oxygen or sulfur atoms, e.g. a chain of a single atom: 0, S, N or C a chain of two atoms: NN, NC, NS, CC or CO or a chain of three atoms: NCN, OCN, CNC, 0C0, NSN, CSN, COC, OCC or CCC, for example: an oxygen atom or a group NR, CO, SO or CR; a group COCO, CONR1, COCR ", SOCR SO NR1, CR" "" CR 1, CR21NR1 or CR120; a group NRxC0NRx, OCONR1, CONREO, C0NR1CR12 / OCOO, CRl20CRxa, OCRx2CO, CRx2C0NR \ CR12CRl2CRi2, COCR ^ CO, CR12NR1CR12, CRx2OCO, or wherein R is hydrogen or a C-alkyl group. or a 1-or alkoxy group optionally substituted by hydroxy, alkoxy, oxa or oxo (eg a polyhydroxyalkyl, formyl, acetyl, hydroxyl, alkoxy or hydroxyalkoxy group), or when linked to a carbon, R can also be a hydroxyl group . Advantageously, the BG group is not symmetric. This can be achieved, for example, by the a-symmetric substitution of a symmetric chain (e.g., N-C-N substituted as NHCONR) or by selection of an asymmetric chain (e.g., OCN substituted as 0C0NR). In particular, it is preferred that the binding group BG be polar and also that it be hydrophilic. Other examples of bridged groups include: -NHC0 (CH2) B CONH-, -NHCO- (CH2OCH2) n-C0NH-, -NHCOCHj (CH2OCH2) nCH2CONH-, -C0NHCH2- (CHOH) BCH2NHCO-, -NH (Ac) CH2 (CHOH) BCH2N (Ac) - and -NHCOCH2CH2SCH2CH2CONH- wherein n is an integer between 1 and 6. This invention also provides novel bismuth compounds of formula III which may be represented as follows: (Illa) (Hlb) The groups in each of the molecules (for example in Illa) can be the same or different, and characteristic groups R -R "are described above. This invention also provides novel bismuth compounds of formula IV which may be represented as follows: (IVa) (IVb) The groups R? -R? in each of the previous molecules (for example in IVa), they may be the same or different and characteristic groups R? _Rp were described above. Bismuth compounds of formula V can be represented, for example, by the following nuclei: The bismuth compounds can be prepared from readily available and cheap bismuth salts. The general synthesis of covalent bismuth compounds is well described in the aforementioned analyzes on bismuth chemistry.

Thus, for example, bismuth compounds of formula I can be synthesized from bismuth (III) chloride as follows: Bismuth compounds of formula II can, for example, be synthesized from derivatives of triiodinated X-ray contrast agents and bismutoxyhydrochloride as follows: orotection Bismuth compounds of formula III (with bismuth oxidation number of 5%). ) can be prepared by halogenation of bismuth compounds of formula I, followed by a Grignard reaction or by using another organometallic reagent such as the lithium salt as illustrated below: , Bismuth compounds of formula IV can be prepared from the dihydrochlorides as follows: For administration to human or animal subjects, the bismuth compounds will be conveniently formulated together with pharmaceutical or veterinary carriers or excipients. The contrast medium of the invention can, conveniently, have pharmaceutical or veterinary adjunct formulations, for example stabilizers, antioxidants, osmolality adjusting agents, regulators, pH-adjusting agents, colorants, seasonings, viscosity adjusting agents and the like. analogues These may be in forms suitable for parenteral or enteral administration, for example, injection or infusion or administration directly into a body cavity having an external evacuation duct, for example the gastrointestinal tract, the bladder and the uterus. Thus, the medium of the invention can be presented in conventional pharmaceutical administration forms such as tablets, coated tablets, capsules, powders, solutions and suspensions, although dispersions in the physiologically acceptable carrier medium, e.g. water for injections, will generally be preferred. When the medium is formulated for parenteral administration, the carrier medium incorporating the bismuth complex is preferably isotonic or somewhat hypertonic. In addition, the medium for parenteral administration may contain small amounts, e.g. 0.01 to 10 percent mole relative to the bismuth compound, free chelating agents or weak chelate complexes with physiologically tolerable chelated species (e.g.

Ca); small additions of sodium or calcium salts can also be advantageously made. For use in X-ray imaging, the medium of the invention will generally have a heavy content of 1 millimole / 1 to 5 mol / 1, preferably 0.1 to 2 mol / 1. Dosages of about 0.05 to 2.0 mmoles / Kg e.g. 0.5 to 1.5 mmol / Kg will generally be sufficient to provide adequate contrast, although dosages of 0.8 to 1.2 mmol / Kg will normally be preferred. For cryptography, dosages of the radioactive species will be generally and significantly low. Polymers with the incorporated bismuth compounds, for example bound to the polymer molecules, can be used in medical catheters. Thus, in summary, the present invention provides particularly effective means in which the efficiency of the contrast medium can be increased by increasing the relative proportion of the molecular volume that is occupied by the heavy atom that increases the contrast or by the metal atom. paramagnetic. For a particular X-ray contrast medium, this also allows the higher K-edge value of the atoms than the iodine of the now conventional X-ray contrast medium to be used effectively. The present invention will now be further illustrated by the following non-limiting Examples (all proportions and percentages are by weight and all temperatures are in degrees Centigrade, unless otherwise specified): Intermediary 1 4-Bromo-l- (2, 5-dimethylpyrrolo) benzene The title compound is prepared according to Bruekelman et al in J. Chem Soc Perkin Trans I (1984) 2801.

Intermediary 2 2- (4-Bromophenyl) -4,4-dimethyl-2-oxazoline 4-bromobenzoic acid (25.32 g, 126 mmol) and thionyl chloride (54 ml) are stirred in benzene (250 ml) under reflux for 24 hours.The solvent is removed under reduced pressure, and the product formed, 4-bromobenzoyl chloride, purified by distillation Production: 23.30 g (88%), p.b. 82-84 ° C (1 mmHg) The 4-bromobenzoyl chloride (20.02 g, 91 mmol) is dissolved in dichloromethane (180 ml) and added dropwise to a solution of 2-amino-2-methyl-1-propanol (19.20 g, 216 mmol) in -dichloromethane (90 ml) at room temperature. hours at room temperature, followed by filtration and removal of the solvent under reduced pressure Thionyl chloride (90 ml) is added dropwise, and the mixture is stirred for 30 minutes at room temperature. The excess of thionyl chloride is removed under reduced pressure and the residue is added to an aqueous solution of HCl (5%, 500 ml). The solution is washed with ether (2x100 ml) and aqueous NaOH (50%) is added until a pH of 9. The basic solution is extracted with ether (3 x 100 ml), and the combined ether solution is washed with water ( 50 ml) and saturated with an aqueous NaCl solution. The dry ether solution (MgSO) is evaporated and the title compound is isolated by distillation. Production: 14.14 g (61%), p. eb 128-130 ° C (1 mmHg). 1 H NMR (200 MHz, CDCl, ..): delta 1.32 (s, 6H), 4.05 (s, 2H), 7.47 (d, 2H), 7.75 (d, 2H).

Intermediary 3 1,2-Bis (dimethylsilyl) benzene 1,2-dibromobenzene (9.37 g, 40 mmol) in dry tetrahydrofuran (25 ml) is added dropwise to a stirred solution of dimethylchlorosilane (7.67 g, 81 mmol), magnesium (2.00 g, 82 mmol) and an iodine crystal. in dry tetrahydrofuran (150 ml). The mixture is refluxed for 4 hours, washed with aqueous HCl (100 ml, 2 M) and then with water (3 x 50 ml). The organic solution is dried (MgSO), the solvent is evaporated and the title product is isolated by distillation. Production 3.87 g (50%), p. eb 54-56 ° C, Rf: 0.69 (silica, hexane: é-ter = 1: 1), MS (EI): 194 (M +).

Intermediary 4 4-bromo-N, N- (1, 2-bis (dimethylsilyl) benzene) añiline Cesium fluoride (2.19 g, 14.4 mmol) is added to a stirred solution of 1, 2-bis (dimethylsilyl) -benzene (Intermediate 3) (3.90 g, 20 mmol) in 1,3-dimethyl-3,4, 5,6-tetrahydro-2 (lH) -pyrimidine (60 ml) at room temperature. The mixture is stirred-for 4 hours at 120 ° C. The cooled reaction mixture is poured into hexane / ether (60 ml, 1: 1), washed with phosphate buffer to pH 7 (3 x 10 ml) and dried (MgSO). The solvent is evaporated under reduced pressure and the residue is recrystallized from methanol / ether. Production: 1.58 g (27%), MS (EI): 361/363.

Intermediary 5 Dimethyl-t-butylsilyl ether of 4-bromo-benzyl alcohol Dimethyl-t-butylsilyl chloride (9.58 g, 65 mmol) is added to a solution of 4-bromobenzyl alcohol (10.0 g, 53 mmol) and imidazole (9.02 g, 133 mmol) in dry dimethylformamide (50 mL). The mixture is stirred at room temperature for 10 hours. Ether (25 ml) and water (25 ml) are added and after phase separation, the organic phase is washed with water, dried (MgSO) and evaporated. Production: 14.3 g (90%).

Example 1 Triphenyl bismuth suspension Human albumin serum (HSA) (3 g) is dissolved in distilled water (150 ml). The solution is filtered through a membrane filter with a pore size of 0.45 micron. A filtered solution (0.22 micron) of triphenyl bismuth (Flu-ka) (1.0 g) in 96% ethanol (25.0 ml) is added slowly to the HSA solution under vigorous stirring for a prolonged period of time. The microparticles formed are centrifuged and washed repeatedly. The particles are dispersed in a sterile isotonic filtrate of 0.9% sodium chloride / water for an injection solution (100 ml) under vigorous stirring until a homogeneous suspension is achieved.

Example 2 Frozen dry powder consisting of a trisodium salt of tris (4-carboxyphenyl) bismuth for dissolution in water before injecting.

Tris (4-carboxyphenyl) bismuth is prepared according to Supnie ski, J. in Rocniki Chem 6 (1926) 97, and the compound (5.0 g) is dissolved in water with the addition of three equivalents of sodium hydroxide. The solution is placed in a 50 ml bottle and dehydrated by freezing.

Example 3 Suspension of dodecafluorodibismatripeiceno (C BipF) A filtered solution of dodecafluorodibismatricecene (0.6 g) in tetrahydrofuran (20.0 ml) is slowly added to an aqueous solution of HSA / propylene glycol under vigorous homogenization.

The microparticles that form are centrifuged and washed repeatedly before the particles are dispersed in a sterile solution of 0.05% polysorbate 80 in a saline solution (5.3 ml).

Example 4 Tris (4-hydroxymethylphenyl) bis utina Trimethylsilyl chloride (1.9 ml, 15 mmol) is added dropwise to a stirred solution of 4-bromobenzyl alcohol (2.0 g, 11 mmol) in toluene (25 ml) and pyridine (2 ml) at 0 ° C. The stirred mixture is heated at room temperature for 3 hours. The reaction mixture is filtered and the organic solution is evaporated to yield 4-bromobenzyltrimethylsilyl ether. The silyl ether can also be purified by distillation (eg, 73 ° C, 0.1 mmHg). Production after distillation: 1.49 g (50%).

The above silyl ether (1.49 g, 5.5 mmol) in tetrahydrofuran (10 ml) is added dropwise to a stirred mixture of magnesium shavings (0.13 g, 5.5 mmol) in tetrahydrofuran (20 ml) containing some iodine crystals. The mixture is heated to reflux until all the magnesium dissolves. Bismuth bromide (III) (0.62 g, 1.4 mmol) is added gradually and the reaction mixture is heated to reflux for 2 hours. The cooled reaction mixture is filtered through a plug of celite followed by the addition of dry tetrabutylammonium fluoride (1.46 g, 5.6 mmol) at 0 ° C. The stirred reaction mixture is heated at room temperature for 2 hours followed by evaporation of the solvent. Chloroform (20 ml) and water (10 ml) are added to the residue and the title compound precipitated as a white talc material. The product is washed with chloroform. Production: 0.22 g (30%) p. fus greater than 300 ° C.

XH NMR (200 MHz, DMS0-dc): delta 4.47 (d, 2H), 5.15 (t, 1H or 7.35 (d.2H) and 7.70 (d, 2H).

Example 5 Tris (4-hydroxyphenyl) bismuthine Trimethylsilyl chloride (11 ml, 87 mmol) is added dropwise to a stirred solution of 4-bromophenol (10.0 g, 58 mmol) in toluene (25 ml) and pyridine (20 ml) at 0 ° C. The stirred mixture is heated at room temperature for 3 hours. The reaction mixture is filtered and the organic solution is evaporated to yield 4-bromophenyltrimethylsilyl ether. The silyl ether can also be purified by distillation (p.b. 122 ° C, 20 mmHg). Production after distillation: 13.70 g (75%).

The above silyl ether (13.70 g, 43 mmol) in tetrahydrofluorine (25 ml) is added dropwise to a stirred mixture of magnesium shavings (1.06 g, 43 mmol) in tetrahydrofuran (25 ml) containing some crystals of iodo. The mixture is heated to reflux until all the magnesium dissolves. Bismuth bromide (III) (4.82 g, 11 mmol) is added gra dually and the reaction mixture is heated to reflux for 2-3 hours. The cooled reaction mixture is filtered through a plug of celite followed by the addition of dry tetrabutylammonium fluoride (11.5 g, 44 mmol) at 0 ° C. The stirred reaction mixture is heated to room temperature - for 2 hours followed by evaporation of the solvent. Chloroform (20 ml) and water (10 ml) are added to the residue and the title compound precipitates as a white crystalline material. The product is washed with cold chloroform. Production: 1.59 g (22.5%) p. fus greater than 300 ° C.

"" "H NMR (200 MHz, DMS0): 6.87 (d, 2H, 8.20 (d, 2H), 9.35 (s, 1H).

Example 6 Tris (4- (2, 5-dimethylpyrrolo) phenyl) bis utina n-Butyllithium in hexane (13.5 ml, 1.5 M, 20 mmol) is added dropwise to a stirred solution of 4-bromo-1- (2,5-dimethyl-pyrrolo) benzene (Intermediate 1) (5.0 g, 20 mmol) in tetrahydrofuran (75 ml) at -78 ° C under an atmosphere of dry argon. After 10 minutes, the solution is warmed to -30 ° C followed by the dropwise addition of a solution of bismuth bromide (III) (2.15 g) in tetrahydrofuran (10 ml). The mixture is stirred for 2.5 hours during heating to room temperature, filtered and the organic solution is evaporated. The residue is recrystallized from benzene. Production: 2.40 g (70%), white crystalline material, p. fus greater than 300 ° C (decomposes). 1 H NMR (300 MHz, CDClg): delta 2.06 (s, 18H), 5.91 (s, 6H), 7. 28 (d, 6H), 7.88 (d, 6H).

Example 7 Tris (4- (4,4-dimethyl-2-oxazoline) phenyl) bismuthine 2- (4-Bromophenyl) -4-dimethyl-2-oxazoline (Intermediate 2) (13.93 g, 55 mmol) dissolved in dry tetrahydrofuran (75 ml), is added dropwise to a suspension of magnesium shavings (1.34 g). , 55 mmol) and a crystal of iodine in tetrahydrofuran (100 ml). The reaction mixture is stirred until all the magnesium chips dissolve. The mixture is added for a further hour at room temperature followed by the dropwise addition of bismuth bromide (III) (6.34 g).13.8 mmol) in dry tetrahydrofuran (10 ml). The reaction mixture is stirred at 55 ° C under an argon atmosphere for one night, followed by filtration through a cellule plug and addition to ice water (200 ml). The mixture is extracted with ethyl acetate (3 x 100 ml), the combined organic phase is dried (MgSO), evaporated and the residual material is subjected to laminar chromatography on silica using a-ethyl acetate: production: 7.48 g (72%), Rf: 0.25 (silica, ethyl acetate), white crystalline material p. fus 233-234 ° C.

"" "H NMR (300 MHz, CDgOD): delta 1.34 (s, 18H), 4.14 (s, 6H), 7. 80 (d, 6H), 7.87 (d, 6H).

Example 8 Tris (4-bromophenyl) bismuthine n-Butyllithium in heptane (2.7 M, 9.25 ml, 50 mmol) is added dropwise to a solution of 1,4-dibromobenzene (5.90 g, 50 mmol) in dry tetrahydrofuran (250 ml) under an atmosphere of dry argon at room temperature. -78 ° C. The mixture is stirred for 1 hour at -78 ° C. A solution of bismuth bromide (III) (2.92 g, 12.5 mmol) in dry tetrahydrofuran (20 ml) is added slowly and the mixture is stirred overnight. After filtration through a plug of celite, the solvent is removed under reduced pressure, and the residue is subjected to lamellar chromatography on silica gel using dichloromethane: hexane (20:80); Production: 3.05 g (72%), Rf: 0.40 (silica, dichloromethane: hexane) (20:80). 13 C NMR (200 MHz, CDCl): delta 122.89, 133.78, 139.02 and 153. 30.

Example 9 Tris (4-ethyloxycarbonylphenyl) bismuthine n-Butyllithium in heptane (4.89 ml, 2.7 M, 13.2 mmol) was added dropwise to a stirred solution of tris (4-bromophenyl) bismutine (from Example 8) (2.71 g, 4 mmol) in dry tetrahydrofuran (40 g). ml) under an argon atmosphere at -78 ° C. The mixture is stirred overnight followed by filtration through a plug of celite and poured into water (50 ml). The mixture is extracted with ethyl acetate (3 x 50 ml), the combined organic solution is dried (MgSO) and the solvent is evaporated under reduced pressure. The white powder is purified by lamellar chromatography to yield 1.03 g (52%) of the title compound as a white crystalline powder.

XH NMR (200 MHz, CDC13): delta 1.36 (t, 9H), 4.35 (q, 6H), 7.54 (d, 6H) and 7.88 (d, 6H).

Example 10 Tris (4-hydroxyphenyl) bismuthine dibromide Bromine (3 mmol, 0.16 mL) is added dropwise to a stirred mixture of tris (4-hydroxyphenyl) bismutine (Example 5) (1.5 g, 3 mmol) in methanol (25 mL) at 0 ° C. The mixture is stirred for 1 hour at room temperature. The solvent is exuded under reduced pressure. The residue is washed with chloroform and the title compound is isolated as a white crystalline material. Production: 1.20 g (62%). 1 H NMR (300 MHz, DMSO-dg); 7.09 (d, 2H), 9.00 (d, 2H), 9.43 (s, 1H).

Example 11 Tris (3, 5-diiodo-4-hydroxy phenyl) bismuthine dibromide Benzyltrimethylammonium dichloroiodate (prepared according to Kajigaeshi et al in Chem Lett. (1987) 2109 (3.49 g, 10 mmol) and sodium acid carbonate, are added to a tris (4-hydroxyphenyl) bismutine dibromide solution. (Example 10) (1.0 g, 1.54 mmol) in a mixture of dichloromethane and me tanol (30 ml, 2: 1) at room temperature The mixture is added for 24 hours at room temperature, and ether (100 ml) is added. add and the organic solution with the precipitate is washed with water, and the title compound is isolated as a white talcum powder Production: 0.43 g (20%) Maximum point shown MS m / e 209 (Bi) - "" H NMR (300 MHz, DMSO-d, ..): 7.53 (s or Example 12 Dextran BiDTPA-aminoethyl for imaging in a blood pool by X-ray Bisphenhydride from DTPA (3.25 g) (prepared from DTPA according to Eckelman in J. Pharm, Sci. 64 (1975) 704) is gradually added to a solution of aminoethyl dextran (MW 80,000, 5.0 g) in dry dimethylsulfoxide (400 ml) at room temperature. The mixture is stirred for 20 hours at the same temperature followed by the addition of water (700 ml). The pH value is adjusted to 5.5, and a solution of bismuth (III) nitrate pentahydrate (4.85 g, 10 mmol) in water (50 ml) is added, the pH value is adjusted to 4.8 and the solution is dialyzed against NaCl 0.9% (w / v) for one week. The aqueous solution is evaporated and the product is dried in a vacuum at 50 ° C. Production: 7.2 g of a white solid material containing 6.0% bismuth.

Example 13 Bismuth (III) chelate of 18 - ((3- (2-carboxybutyl) -2,4,6-triiodophenyl) amino) -3,6,9-tris (carboxymethyl) -ll, 18-dioxo-3, 6, 9, 12-tetraazaoctadecanoic The above chelating agent (prepared according to W094 / 276-44) (20.3 g, 0.02 mol) is dissolved in water (800 ml). The freshly precipitated bismuth hydroxide (0.02 mol) (pre-stopped from the bismuth nitrate pentahydrate and sodium hydroxide) is added, and the mixture is stirred at 100 ° C for 24 hours. The solvent is evaporated under reduced pressure and the title compound is isolated as a white crystalline material.

Example 14 Tris (2,4,6-trimethylphenyl) bismuthine The compound is prepared according to Matano et al. in Bull Chem Soc. Jpn, 65 3504 (1992). Production: 77%.

Example 15 Tris (2,4,6-trimethylphenyl) bismuthine dichloride Thionyl chloride (1.48 g, 11 mmol) is added to a solution of tris (2,4,6-trimethylphenyl) bismutin (Example 14) (5.66 g, 10 mmol) in hexane (100 ml) at room temperature. The mixture is stirred for one hour and the precipitated product is isolated and recrystallized from ethanol. Production: 5.70 g (90%).

XH NMR (300 MHz, CDC13): 2.32 (9H), 2.74 (18H), 7.16 (6H) Example 16 Triphenyl bismuthine difluoride The compound is prepared according to Challenger and Wilkinson in J. Chem Soc. 121: 91 (1922). Production: 75%.

Example 17 Tris (2,6-dimethylphenyl) bismutin 2-bromo-m-xylene (9.25 g, 50 mmol) in ether (15 ml) is added dropwise to a stirred suspension of magnesium (1.22 g, 50 mmol) and some crystals of iodine in ether (20 ml) at 0 ° C. When the Grignard reagent is formed - (4 hours), the mixture is stirred at room temperature for one hour. Bismuth chloride (3.15 g, 10 mmol) is added and the mixture is stirred for 10 hours. The reaction mixture is poured into a saturated solution of ammonium chloride and extracted with ether (3 x 20 ml). The combined organic phase is dried (MgSO) and the solvent is evaporated under reduced pressure. The title compound is recrystallized from ethanol. White solid, production: 1.81 g (35%). 13C NMR (200 MHz CDC13): delta 28.53, 127.17, 127.52, 145.05, 158. 42 Example 18 Tris (4-aminophenyl) bismuthine protected with l, 2-bis (dimethylsilyl) ben-ceno n-Butyllithium in hexane (2.50 ml, 1.6 M, 4 mmol) is added dropwise to a stirred solution of 4-bromo-N, N- (1,2 bis) (dimethylsilyl) benzene) aniline (Intermediate 4) (1.45 g, 4 mmol) in tetrahydrofuran at -78 ° C. The mixture is stirred for 1 hour, a solution of bismuth bromide (0.45 g, 1 mmol) in tetrahydrofuran (10 ml) is added and the reaction mixture is stirred overnight. The mixture is poured into a phosphate buffer pH 7 (50 ml), the aqueous phase is extracted with chloroform (3 x 50 ml), the combined organic phases (tetrahydrofuran and chloroform) are dried (MgSO) and the solvents are e- steam at reduced pressure. The product is recrystallized from hexane / ether and isolated as a white crystalline material. Production: 0.60 g (57%).

Anal .: C: 54.51%, H: 5.79%, N: 4.09% (Calculated: C: 54.57%, H: 5.72%, N: 3.98%) Example 19 Bis (4-hydroxymethylphenyl) bismuth bromide as bis-trimethyl-t-butyl ether Bismuth tribromide (0.95 g, 2.1 mmol) is added to a solution of silyl ether (Intermediate 5) (5.62 g, 6.4 mmol) in tetrahydrofuran (25 ml) at room temperature. The stirred mixture is refluxed overnight, the solvent is evaporated under reduced pressure and the title compound is purified on lamellar chromatography (silica, hexane-ethyl acetate 8: 1). Production: 1.59 g (35%).

H NMR (200 MHz, CDCl): delta 0.17 (s, 12H), 0.99 (s, 18H), 4. 80 (s, 4H), 7.65 (d, 4H), 8.20 (d, 4H) Example 20 p-phenylene-bis (di (4-hydroxymethylphenylbistrutin) as dimethyl-t-butylsilyl ether n-Butyllithium in hexane (1.51 mL, 1.6 M, 2.4 mmol) is added dropwise to a stirred solution of 1,4-dibromo-benzene (0.26 g, 1.1 mmol) in tetrahydrofuran (15 mL) at -78 ° C. . The mixture is stirred for 1.5 hours, the silyl ether of Example 19 (1.59 g, 2.2 mmol) in tetrahydrofuran (10 ml) is added, and the mixture is heated at reflux temperature for one hour. After refluxing for 10 hours, the mixture is extracted with an aqueous solution of sodium chloride (40 ml, 5%) and extracted with water (2 x 10 ml). The dried organic solution (MgSO) is evaporated and the title compound is purified by lamellar chromatography (silica, hexane ethyl acetate 8: 2). Production: 0.67 g (22%).

"" "H NMR (200 MHz, CDC13): delta 0.19 (s, 18H), 1.03 (s, 27H), 4.81 (s, 6H), 7.42 (d, 6H), 7.52 (q, 4H), 7.78 ( d, 6H).

Example 21 Preparation of tetrabenzyl alcohol from Example 20 The silyl ether (from Example 20) is separated with tetrabutylammonium fluoride in tetrahydrofuran.

Example 22 Preparation of tris (4-aminophenyl) bismuthine from Example 18 The silyl derivative (from Example 18) is separated with tetrabutylammonium fluoride according to standard methods in organic chemistry.

Example 23 Activity of bismuth compounds against Helicobacter pylori Several bismuth compounds were tested in different concentrations against Helicobacter pylori on agar plates. The Minimum Inhibitory Concentrations • (MIC - values) are given in mg of substance per liter.

SUBSTANCE No. of EXAMPLE VALUE - MIC Tris chloride (2,4,6- 15 minor or equal trimethylphenyl) -bismutin 0.25 Tris (2, 4, 6-trimethylphenyl) 14 less than or equal to-bismuthine 0.25 16 triphenylbismutin difluoride Tris (2,6-dimethylphenyl) - 17 bismuthine Bismuth subsalicylate 32 bismuth subnitrate It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (19)

1. A contrast medium for the formation of diagnostic images consisting of a covalent bismuth compound of the non-aggregated type.

2. A contrast medium for the formation of diagnostic images according to claim 1, characterized in that the bismuth compound contains at least one additional heavy atom.

3. A contrast medium for the formation of diagnostic images according to claim 1, characterized in that at least one additional atom is selected from iodine, bismuth, lanthanides, transition metals and other metal atoms that are effective diagnostically.

4. A contrast medium for the formation of diagnostic images according to claim 1, characterized in that it consists of a tolerable molecule physiologically selected from the formulas I-IV: wherein the groups R .. - R, - may be the same or different 1 b and are groups that form a hydrolytically stable bond to bismuth, and X is 0, S or NR6 where R6 is lower alkyl, substituted lower alkyl or a aryl group.

5. A contrast medium for the formation of diagnostic imaging according to claim 4, characterized in that R1-R5 are selected from aryl groups substituted with one or more heavy atoms and X is 0, S or NR6 where R6 is low alkyl, substituted lower alkyl or an aryl group.

6. A contrast medium for the formation of diagnostic imaging characterized in that it consists of a non-covalent bismuth compound of the non-aggregated type, with the proviso that the bismuth compound contains at least one additional heavy atom.

7. Use of a bismuth compound according to any of claims 1 to 6, characterized for the preparation of a contrast medium for use in imaging the human or non-human body.

8. A method for generating an image of the human or non-human body, characterized in that it comprises the administration to said body of a physiologically tolerable amount that increases the contrast, of a bismuth compound according to any of claims 1 to 6, as well as the generation of an image of at least a part of said body in which said agent is distributed.

9. A contrast medium for the formation of diagnostic images, characterized in that it consists of a bismuth compound according to any of claims 1 to 6, together with at least one sterile pharmaceutical carrier or excipient.

10. A pharmaceutical composition characterized in that it comprises a bismuth compound according to any of claims 1 to 5.

11. Use of a bismuth compound according to any of claims 1 to 5, characterized for the preparation of a therapeutic agent for the treatment of gastrointestinal disorders.

12. Use according to claim 11, characterized in that the disorder is caused by Heliobac-ter pilori.

13. A method for the treatment of a gastrointestinal disorder in a human or non-human body, characterized in that it comprises the administration, to said body, of a physiologically tolerable dose of a bismuth compound according to any of claims 1 to 5. .

14. A method according to claim 13, characterized in that the disorder is caused by Heliobacter pylori.

15. A covalent bismuth compound of the non-aggregated and hydrolytically stable type, characterized in that it contains at least one additional heavy atom.

16. A covalent bismuth compound of the type that does not form aggregates, characterized in that it contains at least one additional heavy atom, with the proviso that said additional heavy atom is not bromine.

17. A bismuth compound according to claims 15 and 16, characterized in that it contains at least one additional bismuth atom covalently linked.

18. A bismuth compound according to claims 15 and 16, characterized in that it contains at least one covalently bonded iodine atom.

19. Bismuth compounds of formula: